The bromodomain is a characteristic amino-acid motif seen in transcriptional regulatory factors and is believed to be involved in the interactions with other transcriptional regulatory factors. Proteins comprising the bromodomain, normally have one or two (Tamkun et al. (1992) Nuc. Acids Res. 20:2603; Haynes et al. (1992) Nuc. Acids Res. 20: 2603), but as many as five (Nicolas et al. (1996) Gene 175(12):233–240) bromodomain motifs. This motif has been identified in a wide range of animals, for example, in the homeotic gene (Digan et al. (1986) Dev. Biol. 114:161–169; Tamkun et al. (1992) Cell 68: 561–572) of the fruit fly (Drosophila), in the transcriptional regulatory genes of yeasts (Winston et al. (1987) Genetics 115:649–656; Laurent et al. (1991) Proc. Nat. Acad. Sci. USA 88:2687–2691) and in mammals (Denis et al. (1996) Genes and Devel. 10:261–271; Yang et al. (1996) Nature 382:319–324). According to a recent report (Jeanmougin et al. (1997) Trends Biochem. Sci. 22:151–153), 37 bromodomain genes, including 13 human genes are recorded in the database. In addition to the bromodomain motif of amino acid residues 59–63, the sequences adjacent to the motif are also structurally conserved, and furthermore, 4 α-helixes (Z, A, B, and C) are reported to be coded within the long 110 amino acids.
When these bromodomain-comprising transcriptional regulatory factors are compared, they all regulate signal-dependent transcription in actively proliferating cells (Tamkun et al. (1992) Cell 68:561–572; Haynes et al. (1992) Nuc. Acids Res. 20:2603). This characteristic implies that oncogenesis may occur when a gene encoding a bromodomain-containing protein undergoes abnormal regulation. In reality, six bromodomain genes have been experimentally proven to associate with oncogenesis. Three of these genes HRX/ALL-1 (Tkachuk et al. (1992) Cell 71:691–700; Gu et al. (1992) Cell 71:701–708); TIF1 (Miki et al. (1991) Proc. Nat. Acad. Sci. USA 88:5167–5171; Le Douarin et al. (1995) EMBO J. 14:2020–2033) and CBP (Borrow et al. (1996) Nature Genet. 14:33–41) are linked with the gene cleavage points in leukemia. All three of these proteins contain the C4HC3 (also called PHD/LAP/TRX) zinc-finger (Aasland et al. (1995) Trends Biochem. Sci. 20:56–59; Koken et al. (1995) CR Acad. Sci. III, 318:733–739; Saha et al. (1995) Proc. Nat. Acad. Sci. USA 92:9737–9741). Also, there are findings that CBP/P300 interact with p53 (Gu et al. (1997) Nature 387:819–823; Lill et al.(1997) Nature 387:823–827) and other various transcriptional factors, suggesting that CBP and the homologous gene P300 play a key-role in cancer.
The other three genes have been suggested to be linked with cancer in various ways. BRG1 interacts with retinoblastoma protein RB (Dunaief et al. (1994) Cell 79:119–130), inducing formation of flat, growth-arrested cells, and thereby showing a tumor-suppressive activity. RING3 has a homology with the fruit fly (Drosophila) growth control protein fsh (Haynes et al. (1989) Dev. Biol. 134:246–257) and is a serine-threonine kinase having endonuclear autophosphorylation activity. This activity has been reported to be linked to the growth phase of chronic and acute lymphocytic leukemia (Denis et al. (1996) Genes and Devel. 10:261–271). As for P/CAF, it has been reported to inhibit the interaction between E1A and p300/CBP (Yang et al. (1996) Nature 382:319–324). When P/CAF is exogenously expressed on HeLa cells, the cell cycle is inhibited. This is believed to be due to the disruption of the transcriptional regulation of E1A by the binding of P/CAF to p300/CBP. Similar to p300/CBP (Bannister and Kouzarides (1996) Nature 384:641–643), P/CAF has been reported to contain histone acetyl-transferase activity (Yang et al. (1996) Nature 382:319–324).
Thus, regulatory abnormalities of transcriptional regulatory factors comprising bromodomains are envisaged to be closely associated with various diseases, particularly, cancer and other cell-proliferation-linked diseases. Hence, attention has been focused on transcriptional regulatory factors comprising bromodomains in the recent years as novel targets for the treatment of cancer and other cell-proliferation-linked diseases.